Project Summary Cholinergic pathway deficits in Alzheimer?s disease (AD) have been associated with cognitive impairment. The ?4?2* nicotinic acetylcholine receptor (nAChR) is involved in cognitive functions such as attention, learning and memory. PET imaging of ?4?2* nAChR may be sensitive to detect abnormalities in the early stages of mild cognitive impairment (MCI) and AD. At University of California-Irvine (UCI) and University of Wisconsin-Madison (UWM), we are involved in imaging ?4?2* nAChR in aging, Alzheimer?s disease (AD) and neurobiology of learning and memory. During the previous 3-year funding period we have successfully completed initial human PET studies (test-retest and radiation dosimetry) with [18F]Nifene with the following major outcomes: 1) [18F]Nifene requires a 40 min dynamic scan for quantitation; 2) [18F]Nifene is able to detect thalamic radiations (white matter tracts); 3) Females show greater [18F]Nifene binding than males; and 4) No aging effect on [18F]Nifene binding was observed. Since the initial study included only 8 subjects, a larger group of subjects is required in order to confirm the findings of male-female differences and aging using [18F]Nifene. In this 3-year renewal application our goals are: 1) Confirm male-female differences using 32 healthy subjects (16M, 16F) and examine aging effects by grouping 16 (8M, 8F) in their 20?s and 16 (8M, 8F) in their 70?s in all brain regions. This is critical for designing our PET study in AD human subjects and to evaluate males and females separately; 2) In the second goal, in pursuit of translation of [18F]Nifene PET to study AD, we propose to study postmortem brains of AD. Two brain areas have been chosen based on previous findings of their significance, anterior cingulate (with corpus callosum) and hippocampus (containing CA1/subiculum). The latter brain region is known to be an early marker for neurofibrillary tangles (NFT). Thus, it will be important to confirm if there is a correlation between the loss of nicotinic receptors (measured by [18F]Nifene) and the increase in NFT (measured by [18F]MK-6240, currently being used in our human AD PET studies) in this brain region. The AD subjects will be compared with controls and Parkinson?s disease subjects (32 subjects in each group, 16M, 16F). This will help ascertain clinical relevance of [18F]Nifene PET imaging in AD. 3) The third goal is to evaluate degree of binding of [18F]Nifene to the receptor subtypes using knock-out (KO) mice. Both ?2 and ?4 KO will be studied using [18F]Nifene PET and autoradiography and a male-female and aging effect will be evaluated in wild-type (WT) mice. These findings will help design transgenic AD mice model studies in order to study the role of the ?4?2* receptors. This renewal application will help to ascertain that females have greater levels of [18F]Nifene binding, there is no aging effect on [18F]Nifene binding and to measure the extent of change in ?4?2* receptors in postmortem AD brains. This information will be used in the design of [18F]Nifene PET studies in our ongoing imaging PET studies of [18F]MK-6240 NFT in MCI and AD subjects.